The research is directed towards elucidating the mechanisms of signal transduction whereby thyroid autoantibodies affect thyroid growth. The goal is to obtain a better understanding of the mechanisms of goiter pathogenesis in patients with autoimmune thyroid diseases. This project will integrate a comprehensive laboratory evaluation with extensive clinical correlations in an attempt to characterize from a biochemical standpoint distinct categories of patients within the heterogenous grouping of autoimmune thyroid disease. This proposed research will focus on the role of two signal transduction pathways - the phosphoinositide-Ca2+ system and the adenylate cyclase-cyclic AMP systems - in the actions of thyroid growth promoting immunoglobulins (TGIs). The hypothesis is that inositol phospholipid hydrolysis products are important regulators of growth in the thyroid and that some TGIs manifest their effects predominantly via metabolic pathways involving phospholipid metabolism while other TGIs stimulate growth mainly via increasing intracellular levels of cyclic AMP. The specific aims of this proposal are 1) to classify TGIs from different patients as to whether they act by stimulating phosphoinositide hydrolysis or adenylate cyclase or both 2) to probe with pharmacologic agents and by comparison to known growth factors the roles of the phosphoinositide-calcium system and the adenylate cyclase system in the proliferation of thyroid cells. These effects will be studied in a cloned line of functioning thyroid cells derived from normal rat thyroid glands (FRTL-5 cells). These cells will be used to identify immunoglobulins extracted from patient's sera with growth promoting activity and to measure the effects of these TGIs on the generation of inositol phospholipid hydrolysis products (inositoltrisphosphate and diacylglycerol), on the elevation of intracellular free Ca2+ levels and on the accumulation of cyclic AMP. The findings from these studies should further our understanding of goiter pathogenesis in particular and cellular proliferation in general.